We previously described five different stage-specific cellular transforming genes activated in T-\and B-lymphoid leukemias, lymphomas, and myelomas, which are evolutionarily well-conserved between mouse and man. These genes have been detected by transfection of NIH 3T3 cells and analyzed by restriction endonuclease sensitivity. A mouse T-lymphoma gene has been isolated utilizing recombinant DNA technology and is currently being characterized. The isolated clone containing the transforming sequence transforms with high efficiency and it is apparent from current efforts that the size of the gene is between 1 and 2 kilobases. This gene, when used as a molecular probe, appears to identify a small gene family. In collaboration with Dr. Geoffrey Cooper's laboratory, utilizing his chicken bursal gene as a probe, we have isolated a molecular clone containing the human B lymphoma-transforming sequence. This gene is the human analogue of the chicken bursal gene and is the activated cellular transforming gene which we detect by transfection in human African and American Burkitts lymphomas. The human B-lym gene is not homologous to c-myc, and in collaboration with Dr. Philip Leder's laboratory, has been localized to human chromosome 1. Hybridization of this gene to the mouse T-lymphoma gene indicates that they share no homology. Presently, we are continuing to isolate and characterize cellular-transforming genes from the lymphoid series and are further investigating the multistage process of carcinogenesis. The T-LymI gene was isolated from the BALB/c mouse T lymphoma S49 and shares homology with genes encoded in the MHCI region. The protein encoded by this gene is 43 to 44 kilodaltons in size and is a secreted protein. This protein can be immunoprecipitated from the supernates of NIH 3T3 cells transformed by this gene using antisera cross-reactive with MHCI framework regions. Supernates from NIH cells transformed by S49 T-lymphoma DNA and supernates from the tumor cell line itself stimulate NIH 3T3 cells to form colonies in semisolid agar. Preliminary results indicate that the secreted T-LymI protein may also have a mitotic effect on splenic T lymphocytes in short-term assays. This protein shares no homology with IL-2, nor does it replace IL-2 in IL-2-dependent assays. (P)